Proteolytic antibodies are a novel therapeutic modality potentially impacting current antibody- based therapy. The ultimate goal of this project is to develop potent proteolytic human monoclonal antibodies (mAb) against beta Amyloids (Ab) for treatment of Alzheimer's disease. To achieve the objective, a novel approach was developed to produce a yeast intracellular human monoclonal antibody library (iHuMab) that can create 1016 possible unique antibodies. A (beta amyloid) specific monoclonal antibodies with protease activity will be screened using iHuMAbeta library and highly specific and tightly regulated multi-reporter system. At the end of phase I, we expect up to 10 unique A specific proteolytic antibodies will be expressed, purified and characterized. Their A40 specific hydrolysis, binding affinity and neutralization capacity will be validated. In phase II A specific antibodies having the highest affinity and protease activity will be produced in large scale quantities for further testing of A40 neutralization effects in mouse models of Alzhemer's disease. Also in Phase II, the most promising molecules would be subjected to pre-clinical evaluation in animal models, pursuant to submission of an IND application for clinical trials. PUBLIC HEALTH RELEVANCE: Therapeutic monoclonal antibodies are one of the fastest growing biotechnology sectors showing marked success for the treatment of various diseases. Proteolytic antibodies are a potential novel therapeutic that could provide a comparable or better benefit but requiring reduced dosages, therefore reducing the cost while increase efficacy. In this project, iHuMAbeta technology platform is developed to identify human proteolytic antibodies against beta-amyloid peptide, a promising target for the treatment of Alzheimer's Disease.